Controlled release of therapeutic agents has been of considerable interest. Many APIs are rapidly cleared from a patient's or an animal's system, therefore requiring administration of multiple doses of the API in order to maintain therapeutic benefits. Implantable drug delivery devices can obviate the need for repeated dosing and can provide sustained release of the API for prolonged periods.
Many areas of therapeutic drug delivery can benefit from sustained controlled release devices, particularly in chronic or ongoing conditions. For example, arthritis, cancer, epilepsy, AIDS, and conditions necessitating hormone replacement all benefit from continuous release of appropriate drugs.
One particular area in which implantable sustained release devices are of interest is contraception. Interest in contraceptives that could provide unattended, long-term effectiveness has persisted for several decades. In 1966, Dziuk and Cook discovered that steroid hormones passed through polydimethylsiloxane at a low and relatively constant rate. They observed that capsules of that polymer containing estrogen could influence estrus in the ewe for prolonged periods. [Dziuk, P, Cook, B, Endocrinology 78 (1966) 208-211]. Segal and Croxatto proposed in 1967 that subdermal capsules of this polymer may serve as the basis for long-term contraception in women. [Segal, Sheldon, Studies in Family Planning 14 (6/7) (1983) 159-163]. In 1966, the Population Council, a non-profit organization located in New York City, began formal studies embodying this concept. After many years of study, a commercial product termed “Norplant®” was developed.
The original Norplant® product consisted of six silicone capsules containing levonorgestrel (“LNG”), a synthetic hormone known to be effective as a contraceptive. These six capsules were inserted subdermally, usually in the upper arm of patients. Amounts of levonorgestrel passed through the walls of the capsules and subsequent systemic distribution of this hormone was shown to provide effective contraception. However, there were significant side effects associated with use of levonorgestrel in this manner.
Although most women tolerated the device well, a significant percentage discontinued the program during the first year of use. [Coutinho, et al., Contraception 18 (4) (1978) 31.5-333; Coutinho, et al., Contraception 18 (4) (1978) 335-353; Diaz, et al. Contraception 25 (5) (1982) 447-456; Goldzieher, J, Fotherby, K, Eds., Pharmacology of the Contraceptive Steroids, Raven Press (New York) 1994]. Most discontinuations were due to menstrual irregularities, although other side effects were reported. For those women who tolerated the side effects during the first year of use, most reported a decline in severity of disturbances after twelve to eighteen months. [Diaz, S, Pavez, M, Robertson, D. Croxatto, H. Contraception 19 (6) (1979) 557-573; Shaaban, M, Salah, M, Zarzour, A, Abdullah, S, Studies in Family Planning 14 (6/7) (1983) 163-169]
Release rates and drug release profiles were studied. After initial insertion the average release rate of levonorgestrel is approximately 80 μg per day. This declines over twelve to eighteen months and reaches a relatively steady release rate of approximately 30 μg per day for the remainder of the time of use [“Norplant® Release Rate”, The Population Council (1991)]. A threshold dose of 24 μg per day of levonorgestrel was found to be required for contraception, and in another study, a dose of 18 μg per day of levonorgestrel was required for acceptable effectiveness. It is generally acknowledged that a release amount of approximately 30 μg per day of levonorgestrel will prevent conception for most women and, therefore, any release of the steroid above approximately 30 μg per day is unnecessary for efficacy. It is conceded that the relatively high release of levonorgestrel during the first twelve to eighteen months following insertion of Norplant® is likely responsible for adverse symptoms reported by many women. [Primiero, F. and Beliagiano, G, in Goldzieher, J, Fotherbv, K, Eds., Pharmacology of the Contraceptive Steroids, Raven Press (New York) 1994, p. 173]. This elevated release of a drug following administration is known as a “burst”.
To understand the reason for the burst and subsequent decline of release rate until a relatively steady state is achieved, it is necessary to examine the mechanism of interaction between the steroid hormone and the polydimethylsiloxane capsule. Once crystals of levonorgestrel are loaded into the capsule, they begin to dissolve in the capsule walls and migrate to the outer surface. By the time the manufactured capsules are ready for implantation, levonorgestrel has saturated the polymer and accumulated in the walls. Once the saturated capsules are inserted into a patient, there is a rapid release of the drug, resulting in a burst.
Following the burst, water from the patient's body begins to migrate slowly through the walls of the capsule to its interior. This process is very slow and it takes some months before significant amounts of water accumulate in the capsule chamber [Robertson, Dale, in Zatuclrni, G, Goldsmith, A, Shelton, J, Sciarra, J, Long Acting Contraceptive Delivery Systems, Harper Row (Philadelphia) (1983)]. As water reaches the capsule chamber, levonorgestrel crystals begin to dissolve in this accumulated water. The walls of the capsule become saturated with water containing levonorgestrel and transport of levonorgestrel correspondingly becomes limited by its solubility in water. It is at this point, approximately eighteen months after implantation of the capsules, that release of levonorgestrel attains equilibrium and a relatively constant amount of 30 μg per day is released.
There is a need in the art for devices which provide more uniform delivery of chemical agents, which exhibit a reduced burst phase, and for methods of reducing or eliminating the burst associated with delivery devices.